Pediatric cystic fibrosis, azithromycin has some benefit

Treatment with azithromycin was not able to prevent the development of lung damage in young children (up to 3 years) with cystic fibrosis (CF), but it was safe and reduced both inflammation, hospitalization and use of antibiotics. These are the conclusions of COMBAT CF, a Phase 3 study recently published in The Lancet Respiratory Medicine.

Treatment with azithromycin has not been able to prevent the development of lung damage in young children (up to 3 years) with cystic fibrosis (CF)but it proved to be safe and reduced both inflammation, hospitalization and use of antibiotics.

These are the conclusions of KAMP CFa Phase 3 trial recently published in Lancet Respiratory Medicine.

Justification and study design
Lung injuries begin to appear early in young children with CF and then gradually worsen, giving rise to an increase in respiratory symptoms, hospitalization and a deterioration in quality of life, the researchers recall in the introduction to the study.

Inflammation of the airways is thought to represent a significant contributing factor to the observation of the above.

However, the only anti-inflammatory drug recommended for CF – high dose ibuprofen – is not recommended for young children.

Azithromycin is a macrolide that is sometimes used to treat infections in CF patients. The available data also document its anti-inflammatory properties, so its use could represent a therapeutic option to stop inflammation and preserve the lungs in children with CF.

The purpose of the Phase 3 COMBAT CF study was to evaluate the safety of azithromycin in young children with CF and its ability to prevent lung damage from worsening during the first 3 years of life.
The study recruited 107 children (3 years and younger) with CF from one of eight CF centers in Australia and New Zealand.

These were randomized to treatment with oral liquid azithromycin (10 mg / kg) or to placebo three times a week until they reached 3 years of age.

The primary aim of the trial was to evaluate the ability of azithromycin to reduce the severity of respiratory diseases and the proportion of children with developing bronchiectasis – a condition in which the airways in the airways are damaged, usually as a result of the inflammatory process, being healed and thickened over time.

In both cases, the aforementioned processes were measured by CT scans of the breast performed in 104 children.

Main results
The data obtained showed that these goals were not met.

Specifically, the proportion of treated patients who developed bronchiectasis – 50 children (88%) – did not differ significantly from the proportion of children in the placebo group – 44 children (94%).
However, the overall severity of respiratory diseases was low in both groups, with no changes in the overall 1- and 3-year CT scans.
Furthermore, other secondary outcomes were considered significantly improved after treatment with azithromycin.

For example, children randomized to macrolide treatment spent less time in the hospital – 6.3 days less – due to respiratory symptoms (eg pulmonary exacerbations) in each of the observation years under the protocol compared to those in the placebo group.

These children also required fewer injection treatments with antibiotics.

Azithromycin did not lead to general improvements in quality of life, but was able to elicit benefits in terms of physical well-being compared with the placebo group.

The study also included the use of bronchoalveolar lavage to collect lung fluids to analyze the bacterial species present in the lungs of these children.

The analysis showed that the most common bacteria observed in children at the age of 3 years were represented by Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus and some streptococci.

However, the prevalence of these bacteria did not differ significantly between treated and untreated children.

An exploratory analysis was also performed to assess the levels of two lung fluid proteins – neutrophil elastase and IL-8, which are markers of inflammation that have been linked to lung damage in the presence of CF.

The data obtained did not reveal significant differences after one year of life, whereas the levels of both biomarkers were significantly lower in children taking azithromycin after 3 years, suggesting the anti-inflammatory effects of the treatment.

Finally, the use of other treatments, such as hypertonic saline and prophylactic treatments for staphylococci, did not significantly affect the results of the children in any of the treatment arms.

On the safety front, treatment with azithromycin was found to be safe, with a reduced number of side effects, distributed between the 2 study groups.

Overall, the results of this trial suggest that the use of azithromycin is safe and may provide some clinical benefit in young children with CF, especially in those who do not have access to treatments that rely on CFTR protein modulation.

“Although the determination of the mechanism of action of azithromycin in this age group was not among the objectives of the study, the uniqueness and abundance of the information obtained in this study are available to conduct further research in this regard,” they conclude. “.

Nicola Casella

Stick SM et al; COMBAT CF Study Group. Effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomized, double-blind, placebo-controlled clinical trial. Lancet Respir Med. 2022 June 2: S2213-2600 (22) 00165-5. doi: 10.1016 / S2213-2600 (22) 00165-5. Epub prior to printing. PMID: 35662406.

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